Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
  • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
  • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
  • C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C253/00—Preparation of carboxylic acid nitriles
  • C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C253/00—Preparation of carboxylic acid nitriles
  • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
  • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
  • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• This invention relates to processes for the synthesis of 2-amino-4,6- dimethoxybenzamide and other benzamide compounds.
• 2-Amino-4,6-dimethoxybenzamide has been prepared from 4,6-dimethoxyisatoic anhydride.
• the 4,6-dimethoxyisatoic anhydride was, in turn, prepared by a reaction of 4,6- dimethoxyanthranilic acid with phosgene (U.S. Patent No. 4,191,840 and Org. Synth. 1947, 27, 45).
• a different route converts 3,5-dimethoxyaniline to its hydrochloride salt, after which the salt is reacted with oxalyl chloride to give 4,6-dimethoxyisatin.
• the isatin is converted to the target compound via an unstable carboxyl intermediate by reaction with sodium hydroxide and hydrogen peroxide followed by an EDCI/HOBt-mediated coupling to produce 2-amino-4,6- dimethoxybenzamide (WO 2008/92231).
• This invention meets the above-identified needs by providing processes for producing at least one
• R 1 and R 5 each independently represent a hydrogen, a Ci-C 6 alkyl, a hydroxy, or a Ci-C 6 alkoxy;
• R , R , and R each independently represent a hydrogen, a Ci-C 6 alkyl, or a Ci-C 6 alkoxy;
• R 6 and R 7 each independently represent a hydrogen, a Ci-C 6 alkyl, a protecting group, or a directing group;
• X represents a halo moiety or a halo-like moiety; wherein at least one of R 1 and R 5 represent a hydrogen;
• R represents a protecting group or a directing group
• step (ii) the at least one Compound III is combined with at least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a CrC 6 alkyl, or
• the at least one Compound IV is combined with at least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a Ci-C 6 alkyl.
• This invention also meets the above-identified needs by providing processes for producing at least one
• R 1 and R 5 each independently represent a hydrogen, a CrC 6 alkyl, a hydroxy, or a CrC 6 alkoxy;
• R , R , and R each independently represent a hydrogen, a Ci-C 6 alkyl, or a Ci-C 6 alkoxy;
• R 6 and R 7 each independently represent a hydrogen, a CrC 6 alkyl, a protecting group, or a directing group
• X represents a halo moiety or a halo-like moiety
• R 1 and R 5 represent a hydrogen
• R represents a protecting group or a directing group
• step (ii) the at least one Compound III is combined with at least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a Ci-C 6 alkyl, or
• the at least one Compound IV is combined with at least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a CrC 6 alkyl.
• step (iv) the at least one Compound IV is combined with at least one second precipitating agent to precipitate the at least one Compound IV.
• the at least one Compound III is combined with at least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a Ci-C 6 alkyl and the at least one Compound III is combined with at least one third precipitating agent to precipitate the at least one Compound III.
• At least one deprotecting agent such that the protecting group or directing group represented by R is replaced with a hydrogen or a CrC 6 alkyl and the at least one Compound IV is combined with at least one third precipitating agent to precipitate the at least one Compound IV.
• R 1 and R 5 each independently represent a hydrogen, a Ci-C 6 alkyl, a
• R , R , and R each independently represent a hydrogen, a Ci-C 6 alkyl, or a Ci-C 6 alkoxy; and R 6 and R 7 each independently represent a hydrogen or a Ci-C 6 alkyl.
• X represents a halo moiety or a halo-like moiety.
• At least one of R 1 , R 2 , R 3 , R 4 , or R 5 represents a Ci-C 6 alkoxy.
• At least two of R 1 , R 2 , R 3 , R 4 , and R 5 each independently represent a Ci-C 6 alkoxy.
• At least three of R 1 , R 2 , R 3 , R 4 , and R 5 each independently represent a Ci-C 6 alkoxy.
• R 2 and R 4 each independently represent a Ci-C 6 alkoxy
• R 1 and R 3 each represent a hydrogen.
• the Ci-C 6 alkoxy is a methoxy.
• R 2 and R 4 each independently represent a Ci-C 6 alkoxy
• R 1 and R3 each represent a hydrogen
• R 7 represents trifluoroacetyl
• a process according to this invention comprises:
• a process according to this invention comprises:
• a process according to this invention comprises:
• a process according to this invention comprises:
• cyano or "nitrile” refers to a -CN.
• halo moiety or halo-like moiety refers to chloro (CI), bromo (Br), iodo (I), triflate (-OTf), tosylate (-OTs), or mesylate (-OMs).
• alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon.
• hydroxy refers to a hydroxyl (-OH) moiety.
• alkoxy refers to an alkyl moiety having an oxygen moiety attached thereto, e.g. methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, pentoxy, n-hexyloxy and the like.
• intermediate refers to any of Compounds II, III, or IV.
• the invention provides processes for precipitating and/or re- precipitating at least one intermediate produced in the synthesis of Compound I.
• the invention also provides a process for the synthesis of Compound I comprising conducting two or more of the process steps in a one-pot process.
• the steps of protecting, halogenating, cyanating, and deprotecting, as described herein, are carried out in a one-pot process.
• FIG. 1 is an illustration of a process according to this invention for the preparation of 2- amino-4,6-dimethoxybenzamide.
• FIG. 2 is another illustration of a process according to this invention for the preparation of 2-amino-4,6-dimethoxybenzamide.
• the process step wherein at least one Compound II is produced by a process comprising combining at least one Compound V with at least one protecting agent to produce at least one Compound II can be referred to as a "protecting step.”
• Protecting agent refers to any compound or groups of compounds that protects functional groups from unwanted reactions.
• the protecting agent can protect R 5 of compound V during production of Compound II, or can protect R 5 of compound II during the halogenating step.
• Protecting group refers to a protecting agent or part of a protecting agent that is attached to Compounds II, III, IV, or I.
• a protecting group selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.
• Certain processes of this invention rely upon the protective groups to block reactive nitrogen present in the reactants.
• the protecting group exhibits the following characteristics: (i) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; (ii) is selectively removable from the protected substrate to yield the desired functionality; and (iii) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions.
• “Directing group” refers to a protecting agent or part of a protecting agent that influences the reactivity of a compound such that a chemical reaction involving the compound can occur with altered regio selectivity of the compound.
• a wide variety of protecting groups/directing groups are known to those skilled in the art of organic synthesis.
• Non-limiting examples of suitable protecting groups/directing groups can be found in Wuts et al. (2007) Greene's Protective Groups in Organic Synthesis, 4th Ed. (John Wiley & Sons, Inc., New York).
• amino-protecting group and “nitrogen protecting group” are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures.
• a protecting agent one skilled in the art would understand which portion of the protecting agent will be attached, i.e. the protecting group, to the compound to be protected.
• a protecting group one skilled in the art could deduce the necessary protecting agent to achieve the resulting protecting group.
• trifluoroacetic anhydride may be referred to as the protecting agent and trifluoroacetyl is the protecting group.
• an acid chloride may be referred to as the protecting agent; for example benzoyl chloride can be referred to as the protecting agent, in which case benzoyl is the protecting group.
• protecting group “protecting group”, “directing group”, “protective group”, or “protecting agent” may be used interchangeably and one skilled in the art would understand the relationship of the protecting agent to the protecting group or directing group.
• a protecting agent it includes all of the resulting protecting group or directing group and when referring to a protecting group or directing group, it also includes all of the protecting agent to create the resulting protecting group.
• Non-limiting exemplary protecting agent or its corresponding protecting groups or directing groups include acetyl, monohaloacetyl, dihaloacetyl, and trihaloacetyl (wherein the halo moiety may be the same or different for each dihaloacetyl and trihaloacetyl group), acetamido, benzyl (Bn), benzoyl (Bz), benzyloxycarbonyl
• protecting group refers to a compound where at least one of its functional group is a protecting group or a directing group.
• the protecting group or directing group is an acetyl. [0041] In another embodiment, the protecting group or directing group is a monohaloacetyl.
• the protecting group or directing group is a dihaloacetyl.
• the protecting group or directing group is a trihaloacetyl.
• the protecting group or directing group is trifluoro acetyl. It has been discovered that the trifluoroacetyl protecting/directing group results in an improved selectivity over the acetyl protecting/directing group during the halogenating step.
• the preparation for the synthesis of Compound I comprises combining Compound V with at least one protecting agent to produce a protected Compound II. It is to be understood that one skilled in the art of organic synthesis could follow the methods described or exemplified herein to determine if providing an already protected Compound II, or protecting a Compound V to produce a protected Compound II, is necessary to synthesize Compound I.
• the protecting step reaction can be carried out under any reaction time, pressure, temperature, solvent, pH condition, concentration, reagents ratio/amount, and any other chemical reaction conditions that are suitable to provide the desired protecting/directing effect. It is understood that one skilled in the art, given the teachings of this specification, can determine and/or optimize the reaction time, pressure, temperature, solvent, pH condition, concentration, reagent ratio/amount, and any other chemical reaction conditions suitable for the protecting step.
• Compound I is 2-amino-4,6-dimethoxybenzamide and Compound V is 3,5-dimethoxyaniline.
• the synthesis of 2-amino-4,6-dimethoxybenzamide comprises protecting 3,5-dimethoxyaniline with at least one protecting agent to produce a protected Compound II.
• the protecting step in this example comprises combining 3,5-dimethoxyaniline with
• Methyl tertiary-butyl ether can be used as a solvent in place of, or in addition to, toluene.
• Other suitable solvents may also be used. Given the teachings of this disclosure, one skilled in the art can select one or more other suitable solvents.
• a solution comprising the toluene or other solvent is taken directly to the next step, i.e. the halogenating step, following aqueous washes.
• a solution comprising the toluene or other solvent is taken directly to the next step, i.e. the halogenating step, without any aqueous washes.
• one skilled in the art may remove, reduce, or increase the toluene or other solvent and/or other intermediates, and/or remove water before halogenating Compound II, e.g. removal of water via azeotropic distillation of the toluene or other solvent and water.
• the process step wherein at least one Compound III is produced by a process comprising combining at least one Compound II with at least one halogenating agent to produce at least one Compound III can be referred to as the halogenating step.
• Halogenating agent refers to any compound that is capable of reacting with
• Halo-like moiety refers to any group that behaves similarly to a halo moiety in terms of reactivity.
• halo-like moieties include triflate (-OTf), mesylate (-OMs), and tosylate (-OTs).
• halogenating agents include I 2 , IC1, IC1 3 , IBr, Br 2 , BrCl, Cl 2 , N-chlorosuccinimide, N-bromosuccinimide (NBS), l,3-dibromo-5,5-dimethylhydantoin (DBDMH), TsCl, tosyl anhydride, MsCl, triflic chloride, and triflic anhydride.
• NSS N-chlorosuccinimide
• N-bromosuccinimide N-bromosuccinimide
• DBDMH l,3-dibromo-5,5-dimethylhydantoin
• TsCl tosyl anhydride
• MsCl triflic chloride
• triflic anhydride triflic anhydride.
• the amount of halogenating agent used should be stoichiometric with the desired product, as will be familiar to those skilled in the art.
• the halogenating agent is NBS.
• the halogenating agent is N-chlorosuccimimide.
• the halogenating agent is DBDMH.
• the halogenating agent is selected from I 2 , IC1, IC1 3 , IBr, Br 2 , BrCl, and Cl 2 .
• the halogenating agent is selected from TsCl, tosyl anhydride, MsCl, triflic chloride, and triflic anhydride.
• the halogenating step may be carried out at any temperature range above the freezing point and below the boiling point of the selected solvent. It is desirable to optimize the temperature and solvent conditions in accordance with solubility considerations of the Compound II when subjected to the halogenating agent.
• the temperature range is from about -65 °C to about 100 °C.
• the temperature range is from about -65 °C to about 50 °C.
• the temperature range is from about -65 °C to about 10 °C.
• the temperature range is from about -10 °C to about 10 °C.
• the temperature range is from about -10 °C to about 5 °C.
• the temperature range is from about -5 °C to about 5 °C.
• the temperature range is from about 0 °C to about 5 °C.
• the protected aniline (3,5- dimethoxytrifluoroacetanilide) compound is reacted with at least one halogenating agent as shown, N-bromosuccinimide (NBS), at a temperature range from about -5 °C to 0 °C to produce halo isomers (e.g. bromo-3,5-dimethoxytrifluoroacetanilide isomers).
• NBS N-bromosuccinimide
• the halogenating step solvent can comprise toluene.
• MtBE and/or dimethylacetamide (DMAc) can be used as a halogenating step solvent in place of, or in addition to, toluene.
• DMAc dimethylacetamide
• Other suitable halogenating step solvents can also be used. Given the teachings of this disclosure, one skilled in the art can select one or more other suitable solvents.
• the halogenating step produces various halo isomers.
• the halogenating step can produce isomers wherein the halo, or as shown, the bromo, is at the 4-position, 2-position, both at the 2- and 4- positions, and both the 2- and 6- positions. It is understood that there could be other isomers produced depending on Compound II, the halogenating agents and conditions used.
• the succinimide by-products are removed by any known means in the arts, such as washing the batch with water.
• the solvent e.g., toluene
• the solvent may be removed using any known methods such as distillation or vacuum.
• the solution of brominated, protected aniline (bromo-3,5- dimethoxytrifluoroacetanilide) in DMF is used in the cyanating step.
• the halogenating step comprises reacting 3,5- dimethoxytrifluoroacetanilide with at least one halogenating agent such as N-bromosuccinimide BS) in chlorobenzene to produce 2-bromo-3,5-dimethoxytrifluoroacetanilide and its isomers.
• the isomers may be removed or separated from solution before the cyanating step.
• the isomers are not removed or separated from solution before conducting subsequent reaction process.
• the protecting step and the selection of the protecting agent can improve the regioselectivity of Compound III.
• the protecting agent improves, or results in higher, regioselectivity of a 2-halo isomer of Compound III over the other isomers such as the 4-halo isomer.
• the halo moiety is bromo
• the process step wherein Compound IV is produced by the process comprising combining at least one Compound III with at least one cyanating agent to produce at least one Compound IV is referred to herein as the cyanating step.
• the cyanating step comprises combining the halo-isomers of the halogenating step with at least one cyanating agent to produce cyano-isomers.
• the bromo-isomers of Compound III including 2-bromo-3,5-dimethoxytrifluoroacetanilide, in DMF are combined with copper (I) cyanide at a temperature range from about 98°C to about 120 °C to produce
• K 4 Fe(CN)6 together with a suitable catalyst, such as Cul at greater than 100 mole%, is used as the cyanating agent.
• DMF is removed using any known means such as distillation to concentrate the batch.
• the concentrated DMF solution is transferred into a solution of ethylenediamine and water to perform the deprotecting step and removal of copper salts.
• Compound IV such as 2-amino-4,6-dimethoxybenzonitrile, is isolated by filtration and dried under a stream of nitrogen.
• the 2-isomer is isolated out of solution or precipitates out, while the non-favored isomers are not isolated out of the solution. It is an advantage of this invention that the desired isomer is isolated and the undesired isomers (4-, 2-/4-, and 2-/6- isomers), which are considered impurities, are not isolated.
• the cyanating step comprises precipitating 2-amino-4,6- dimethoxybenzonitrile.
• the process provided results in the precipitation of the desired 2- amino-4,6-dimethoxybenzonitrile intermediate product, resulting in lower isomeric impurities.
• the one-pot process improves cost and time factors for improved efficiency without the need to purify and isolate at each intermediate reaction.
• Compound IV is combined with at least one deprotecting agent and first precipitating agent, such as ethylenediamine and water.
• first precipitating agent such as ethylenediamine and water.
• the favored isomer i.e. 2-amino- 4,6-dimethoxybenzonitrile, precipitates out of solution while the other isomers remain in solution.
• the cyanating step can be carried out under any reaction time, pressure, temperature, solvent, pH condition, concentration, reagents ratio/amount, and any other chemical reaction conditions that are suitable to add at least one cyano (-CN) moiety to Compound III or replace at least one halo moiety with at least one cyano group on Compound III. It is understood that one skilled in the art can determine and/or optimize the reaction time, pressure, temperature, solvent, pH condition, concentration, reagent ratio/amount, and any other chemical reaction conditions suitable for the cyanating step.
• the temperature range for the cyanating step may be from about 50 °C to about 155 °C.
• the temperature range for the cyanating step may be from about 50 °C to about 120 °C.
• the temperature range for the cyanating step may be from about 50 °C to about 105 °C.
• the temperature range for the cyanating step may be from about 98 °C to about 105 °C.
• Cyanating agent refers to any compound which when reacted with Compound III can replace at least one halo moiety with a cyano group or add at least one cyano moiety to Compound III.
• Non-limiting examples of cyanating agent includes Zn(CN) 2 , CuCN, NaCN, KCN, Cu(CN) 2 , Ni(CN) 2 , iron cyanide and other agents of the like. Cyanating may be carried out with or without a catalyst, e.g., a cyanating agent may comprise a catalyst.
• the cyanating agent is CuCN.
• the cyanating agent comprises K 4 Fe(CN) 6 and Cul.
• the cyanating agent comprises Na 4 Fe(CN) 6 and CuBr.
• the cyanating agent comprises K 4 Fe(CN)6 and CuBr.
• the cyanating agent comprises Na 4 Fe(CN)6 and Cul.
• deprotecting refers to the removal of at least one protecting group or directing group.
• Deprotecting agent refers to any compound that can remove at least one protecting group or directing group.
• Non-limiting deprotecting agents include ethylenediamine, ammonia, ethanolamine, and methylamine.
• the deprotecting step is carried out before the cyanating step.
• the deprotecting step is carried out after the cyanating step.
• the deprotecting step is carried out simultaneously with the cyanating step.
• the deprotecting step can also be carried out partially before the cyanating step and/or partially during the cyanating step and/or partially after the cyanating step.
• any of the cyanating step and deprotecting step and precipitating step can be conducted in a one-pot process.
• the process step wherein the at least one Compound III is combined with at least one third precipitating agent, or wherein the at least one Compound IV is combined with at least one first or third precipitating agent, is referred to herein as the precipitating step.
• first precipitating agent refers to any substance that promotes or causes a Compound IV to precipitate out of solution.
• the resulting precipitate can comprise crystalline structures and/or amorphous structures.
• a non-limiting example of a suitable first precipitating agent is water. In light of the teachings of this specification, other suitable first precipitating agents will be familiar to those skilled in the art.
• third precipitating agent refers to any suitable non-polar solvent or other suitable substance that promotes or causes a Compound III or a Compound IV to precipitate out of solution.
• the resulting precipitate can comprise crystalline structures and/or amorphous structures.
• a non-limiting example of a suitable third precipitating agent is heptane.
• other suitable third precipitating agents will be familiar to those skilled in the art.
• deprotecting and precipitating are done in the same step.
• ethylenediamine and heptane are used to promote deprotecting and precipitating of Compound III.
• ammonia and heptane are used to promote deprotecting and precipitating of Compound III.
• ethanolamine and heptane are used to promote deprotecting and precipitating of Compound III.
• methylamine and heptane are used to promote deprotecting and precipitating of Compound III.
• ethylenediamine and water are used to promote deprotecting and precipitating of Compound IV.
• ammonia and water are used to promote deprotecting and precipitating of Compound IV.
• ethanolamine and water are used to promote deprotecting and precipitating of Compound IV.
• methylamine and water are used to promote deprotecting and precipitating of Compound IV.
• the precipitating step is carried out after the cyanating and deprotecting steps.
• second precipitating agent refers to any substance that promotes or causes a Compound IV to precipitate out of solution, following at least one previous precipitation of Compound IV with either a first precipitating agent or a third precipitating agent, in accordance with this invention.
• the resulting precipitate can comprise crystalline structures and/or amorphous structures.
• a non-limiting example of a suitable second precipitating agent is isopropyl alcohol. In light of the teachings of this specification, other suitable second precipitating agents will be familiar to those skilled in the art.
• the re-precipitating step may also result in purification of the Compound IV precipitate.
• the hydrating step comprises combining Compound IV with at least one hydrating agent and/or at least one hydrating catalyst to produce at least one
• Compound I is referred to herein as the hydrating step.
• the hydrating step reaction can be carried out under any reaction time, pressure, temperature, solvent, pH condition, concentration, reagents ratio/amount, and any other chemical reaction conditions that are suitable to remove or substitute at least one cyano moiety from Compound IV. It is understood that one skilled in the art can determine and/or optimize the reaction time, pressure, temperature, solvent, pH condition, concentration, reagent ratio/amount, and any other chemical reaction conditions suitable for the hydrating step.
• the hydrating step comprises converting at least one cyano moiety into at least one carboxamide.
• the hydrating step may be carried out at a temperature range from about 70 °C to about 150 °C.
• the hydrating step may be carried out at a temperature range from about 100 °C to about 115 °C.
• the process for the synthesis of 2-amino-4,6-dimethoxybenzamide comprises hydrating 2-amino-4,6-dimethoxybenzonitrile with at least one hydrating agent such as methanesulfonic acid.
• the hydrating step further comprises re-precipitating 2-amino-4,6- dimethoxybenzonitrile before contacting it with a hydrating agent.
• the reaction is conducted for about two hours of heating (approximately 1-2 hours at temperatures between 100-115 °C).
• hydrating the nitrile compound further comprises adding water and dichloromethane (DCM) to the acidic mixture.
• DCM dichloromethane
• the choice of solvent is not limited to the preceding examples, but is dependent on the structure of the compound of interest among other factors.
• One skilled in the art may use alternate solvents that do not react with the compound of interest, such as but not limited to ethyl acetate, isopropyl acetate, ether such as 2- methyltetrahydrofuran, alcohol such as isopropyl alcohol, and other solvents or combinations of solvents of the like.
• the hydrating step further comprises neutralizing the batch by contacting about 50% caustic and adjusting the pH range from about 3 to about 12.
• neutralizing agent may be used to adjust the pH as desired.
• the pH range may be from about 6.0 to about 8.0. In another embodiment, the pH range may be from about 6.5 to about 7.3.
• the hydrating step further comprises an extracting step.
• the extracting step comprises extracting the aqueous layer with DCM three times and the organic layer is washed twice with water to remove methanesulfonate salts. Distillation of
• dichloromethane occurs to reduce the overall batch volume and the batch is slowly cooled to a temperature range from about 23 °C to about 28 °C.
• MtBE is charged to the batch and it is further cooled down to a temperature range from about -5 °C to about 0 °C.
• the product 2- amino-4,6-dimethoxybenzamide is isolated by any means such as by filtration and dried under a stream of nitrogen.
• One skilled in the art may use another type of solvent for extraction that does not adversely affect the reactions such as isopropyl acetate, ethyl acetate, isopropyl alcohol, 2-methyltetrahydrofuran, or combinations thereof.
• a solvent exchange occurs until there is less than 1% halogenated solvent remaining in the pot.
• a non-halogenated solvent may be used following neutralization, thereby potentially eliminating the need for solvent exchange.
• the volume is reduced via distillation until the desired volume range of IP Ac, IPA, ethyl acetate, methyl THF, or alternate solvent is achieved.
• an appropriate anti- solvent such as MtBE or heptane, is optional. However, yield improvement is observed with an appropriate anti-solvent.
• 2-amino-4,6-dimethoxybenzamide is prepared comprising hydrating 2-cyano-3,5-dimethoxytrifluoroacetanilide with a hydrating agent such as
• the preparation of 2-amino-4,6-dimethoxybenzamide comprises
• Hydrating agent refers to any compound which when combined with Compound IV can convert at least one cyano group into a carboxamide group or hydrate the triple bond of the cyano group.
• Hydrating agent also includes hydrating catalysts.
• the term "hydrating catalyst” refers to any compound that promotes and/or assists in hydrating Compound IV to Compound I.
• Non-limiting examples of hydrating agents include water, ferric nitrate, alcohols, acids such as sulfuric acid, trifluoroacetic acid, methanesulfonic acid, phosphoric acid such as polyphosphoric acid, bases such as NaOH, KOH, cesium hydroxide, barium hydroxide, metal catalyst, the like, and combinations thereof.
• the hydrating step converts the cyano group into a carboxamide group while minimizing the amount of carboxylic acid produced.
• the hydrating step is carried out under acidic reaction conditions.
• the hydrating step may also be carried out under basic reaction conditions.
• the reactions of the synthetic methods claimed herein are carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis, said suitable solvents generally being any solvent which is substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
• a given reaction can be carried out in one solvent or in a combination of two of more solvents.
• suitable solvents for a particular reaction step can be selected by one skilled in the art.
• the functional groups or moieties of the present invention include substituted or non- substituted, protected or non-protected moiety.
• substituted or non- substituted, protected or non-protected moiety When a particular group is "substituted" that group may have one or more substituents, from one to five substituents, from one to three substituents, from one to two substituents, independently selected from the list of substituents.
• some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
• some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
• Trifluoroacetic anhydride (185 g) was added over at least 1 hour maintaining a reaction temperature of 18-25 °C. The reaction was stirred for at least 1 hour and then checked by HPLC for reaction completion. Water (250 g) was loaded to the batch and the reaction was heated to 40-45 °C and stirred for at least 10 minutes. The agitation was stopped and the phases were separated. The bottom aqueous phase was removed and water (250 g) was loaded to the toluene product layer. The batch was stirred at 40-45 °C for at least 10 minutes and the phases were separated by removing the bottom aqueous phase.
• the 3,5-dimethoxytrifluoroacetanilide product toluene solution was then cooled to less than 0 °C in preparation for the bromo-3,5- dimethoxytrifluoroacetanilide step of the process.
• the solution was heated to reflux and toluene was distilled until a pot temperature of 125-140 °C was obtained.
• the batch was cooled to less than 80 °C under nitrogen and N',N'-dimethylformamide (DMF) (1215 g) was loaded to the pot.
• the batch was agitated and cooled to less than 80 °C. This solution was used in the 2-amino-4,6-dimethoxybenzonitrile step of the process.
• DMF N',N'-dimethylformamide
• the batch was held at 5-15 °C for 2 hours and then the 2-amino-4,6-dimethoxybenzonitrile product was isolated by filtration.
• the 2-amino-4,6-dimethoxybenzonitrile cake was washed with water to remove the mother liquor.
• the final wet cake was dried and analyzed by HPLC. The process produced 123 grams of 2- amino-4,6-dimethoxybenzonitrile product in a yield of 88% from the starting 3,5- dimethoxyaniline .
• the resulting slurry was cooled slowly to 0-5 °C over at least 2 hours.
• the batch was held at 0-5 °C for at least 0.5 hours and filtered to harvest the product.
• the 2-amino-4,6-dimethoxybenzonitrile cake was washed with isopropyl alcohol and dried in a vacuum oven at 50 °C and 22 inches of vacuum.
• the process produced 83.8 grams of purified 2-amino-4,6-dimethoxybenzonitrile in 84% yield.
• DCM/MtBE is 1:3.2; total volumes of solvent is 18.9).
• the batch was slowly cooled to between -5 °C and 5 °C over at least 3 hours.
• the batch was held for at least 1 hour between -5 °C and 0 °C.
• Precipitation was verified through collection of at least two samples from the liquor to determine the amount of 2-amino-4,6-dimethoxybenzamide remaining in solution.
• the batch was isolated by filtration and the wet cake washed with a cold (0 °C) mixture of 1:4
• alternate solvents include, but are not limited to esters like isopropyl acetate and ethyl acetate, and ethers like 2-methyltetrahydrofuran.
• alternate precipitation systems with or without anti- solvent have also been examined.
• the precipitation system may include, but is not limited to esters like isopropyl acetate, ethers like 2-methyltetrahydrofuran, and alcohols like isopropyl alcohol.
• the yield range from these modifications in the experimental procedure is 72-79%.
• purity of the desired compound is consistently over 99%.
• the first organic phase cut was performed.
• the aqueous layer was extracted two additional times with DCM (371 mL and 286 mL respectively).
• Dichloromethane (271 mL) was added to the combined organic layers and the organic layer was washed with water (714 mL) to remove methanesulfonate salts.
• Dichloromethane (79 mL) was added to the combined organic layers and the organic layer was washed once more with water (714 mL) to remove methanesulfonate salts.
• the batch was distilled using (5-10 inches Hg) vacuum to a pot volume of 6 volumes DCM (300 mL).
• Solvent exchange with isopropyl acetate was completed when less than 1-2% DCM remained and the pot volume was between 400-450 mL.
• the contents of the vessel were stirred for 1 hour at 85-90 °C.
• the vessel was cooled to 50 °C over at least 2 hours with slow agitation.
• the vessel was slowly charged with MtBE (250 mL) and the batch was agitated for 30 min at 50 °C.
• the batch was slowly cooled to 30 °C over at least 1 hour.
• the batch was cooled to -5 °C and 5 °C over at least 2 hours.
• the batch was held between -5 °C and 5 °C over at least 1 hour.
• a reaction sample was added to sodium thiosulfate solution and the organic layer analyzed by GC.
• Water 100.01 g was added to the reaction mixture and the mixture was agitated. The aqueous layer was removed and the organic layer was then washed twice more with water (101.08, and 100.94 g). The solvent was removed by rotary evaporation in vacuo to yield an off-white solid (63.04 g).
• Trifluoroacetic acid (6.52 g, 4.4 mL) was charged to a flask equipped with a magnetic stirring bar and thermocouple. Sulfuric acid (96%, 9.2 g, 5mL) was charged to the flask. In small portions 2-amino-4,6-dimethoxybenzonitrile (1.01 g, -76% pure) was charged to the mixed acid solution in the flask. A condenser was added and the solution was heated at 75 °C for 17 h. After the dark mixture had cooled to room temperature it was charged to water (9.79 g) cooled in a large ice bath while maintaining the reaction temperature below 10 °C. Concentrated ammonium hydroxide (19.37 g) was added dropwise to the cooled solution (reaction
• the batch was agitated and heated to 80 °C. External heating was removed and the batch cooled to 20-25 °C.
• the precipitated bromo-3,5- dimethoxytrifluoroacetanilide was isolated by filtration, washed with heptane (100 mL) and dried in a vacuum oven at 50 °C. The process produced 99.6 grams of bromo-3,5- dimethoxytrifluoroacetanilide in 93% yield.
• This example provides various conditions in accordance with the present invention for the conversion of 2-amino-4,6-dimethoxybenzonitrile to 2-amino-4,6-dimethoxybenzamide.
• the main routes for hydrating are: acidic, basic, and catalytic (involving a catalyst in addition to another reagent), or use of various groups of metals to facilitate the reaction.
• the reaction time varies. In the following conditions, the optimal reaction temperature range is from about 100 °C to about 115 °C, with reaction completion in 1 hour to 2 hours.
• 2-amino-4,6-dimethoxybenzonitrile (2-amino-4,6-dimethoxybenzonitrile), CH 3 SO 3 H, with or without A1 2 0 3 , workup with KOH and/or 50% caustic and/or phosphate buffer and/or 30% potassium carbonate at 120 °C for 2-4 hours. Product not isolated. Conversion to 2-amino- 4,6-dimethoxybenzamide: 78-88% (by HPLC).
• reactants and components referred to by chemical name or formula anywhere in this document, whether referred to in the singular or plural, are identified as they exist prior to coming into contact with another substance referred to by chemical name or chemical type (e.g., another reactant, a solvent, or etc.). It matters not what preliminary chemical changes, transformations and/or reactions, if any, take place in the resulting mixture or solution or reaction medium as such changes, transformations and/or reactions are the natural result of bringing the specified reactants and/or components together under the conditions called for pursuant to this disclosure.
• the reactants and components are identified as ingredients to be brought together in connection with performing a desired chemical operation or reaction or in forming a mixture to be used in conducting a desired operation or reaction.
• an embodiment may refer to substances, components and/or ingredients in the present tense ("is comprised of”, “comprises”, “is”, etc.), the reference is to the substance, component or ingredient as it existed at the time just before it was first contacted, blended or mixed with one or more other substances, components and/or ingredients in accordance with the present disclosure.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Health & Medical Sciences (AREA)
• Toxicology (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Priority Applications (15)

Applications Claiming Priority (4)

Publications (2)

Family

ID=49447844

Family Applications (1)

Country Status (16)

Cited By (4)

Families Citing this family (1)

Citations (4)

Family Cites Families (9)

• 2013
  • 2013-10-09 ES ES13779704.9T patent/ES2664050T3/es active Active
  • 2013-10-09 US US14/237,600 patent/US9346743B2/en active Active
  • 2013-10-09 MX MX2015004325A patent/MX348338B/es active IP Right Grant
  • 2013-10-09 CN CN201380053579.1A patent/CN104918912B/zh active Active
  • 2013-10-09 KR KR1020157011968A patent/KR101991148B1/ko active IP Right Grant
  • 2013-10-09 WO PCT/US2013/063995 patent/WO2014062428A1/en active Application Filing
  • 2013-10-09 RU RU2015118164A patent/RU2650110C2/ru active
  • 2013-10-09 BR BR112015008171-1A patent/BR112015008171B1/pt active IP Right Grant
  • 2013-10-09 IN IN2588DEN2015 patent/IN2015DN02588A/en unknown
  • 2013-10-09 CA CA2886973A patent/CA2886973C/en active Active
  • 2013-10-09 NZ NZ707115A patent/NZ707115A/en unknown
  • 2013-10-09 EP EP13779704.9A patent/EP2906530B1/en active Active
  • 2013-10-09 JP JP2015536850A patent/JP6289479B2/ja active Active
  • 2013-10-09 AU AU2013331731A patent/AU2013331731B9/en active Active
• 2015
  • 2015-03-29 IL IL238003A patent/IL238003A/en active IP Right Grant
  • 2015-04-13 SA SA515360281A patent/SA515360281B1/ar unknown

Patent Citations (5)

Non-Patent Citations (2)

Also Published As

Similar Documents

Legal Events